We are interested in how animals use particular genes and signalling networks to control their physiology development, and behaviour. Much of our work focuses on signalling through the second messengers IP3 (inositol 1,4,5-trisphosphate) and calcium. Our current interests include:
- Presenilins, calcium signalling and Alzheimer's disease
- Regulation of RNAi
- IP3 signalling in development, physiology and behaviour
Most inherited forms of Alzheimer’s disease are caused by mutations in a group of proteins called presenilins. We have shown that C. elegans with presenilin mutations have hitherto undetected changes in the function of the nervous system. This is important as it is changes in the nervous system that underlie Alzheimer’s disease. We now wish to understand this function in more detail. In addition to changes in the processing of amyloid precursor protein, cells from Alzheimer’s patients have changes in calcium homeostasis. We are using C. elegans to understand how presenilins regulate IP3 signalling and thus cause changes in calcium homeostasis
Regulation of RNAi by IP3 signalling
We have shown that changes in IP3 signalling alter the sensitivity of worms to RNAi. Opening up the possibility that environmental and physiological changes alter an animals RNAi response.
We are now:
a) Investigating the mechanism
b) Testing whether other small RNA mediated processes are also altered
How do the structural characteristics of the IP3 receptor relate to whole animal function? In vivo structure function studies.
We have developed a system that enables us to make specific changes in the itr-1 gene, which we can then reintroduce into C. elegans. We can then measure the known IP3 mediated processes in these animals and thus determine to what extent the change affects each process. This means that we can now ask how important specific sites in the IP3 receptor are to particular roles in a whole animal. We are using this system to address the importance of protein interaction sites identified in work on mammalian IP3Rs to IP3 signalling in whole animal function.
IP3 signalling in nervous system
Although it is well known that C. elegans mutants in both heterotrimeric G-proteins and phospholipase C molecules that would be expected to regulate IP3 production have widespread neuronal dysfunction, remarkably little is known about the role of IP3 signalling in the C. elegans nervous system. Using a range of transgenic and genetic approaches we have ablated IP3 signalling in the nervous system and parts of the nervous system. We have established roles for IP3 signalling in mechansosensation and in some specific chemosensory functions in the polymodal sensory neurone ASH. One of these functions may involve a novel mechanism of IP3 receptor activation, which we now wish to understand. We have also identified more widespread roles for IP3 signalling in the nervous system, requiring further study.
IP3 signalling in development
IP3signalling mutants have a number of developmental defects (Walker et al, 2002). The Hardin lab showed that these include defects in morphogenesis. We are looking at a number of questions concerning the role of IP3 signalling in embryos. We recently established that the phospholipase C gene plc-1 is required for proper morphogenesis (Vázquez et al, 2008). PLC-1 is the homologue of mammalian PLC-ε and is intriguing because it has a complex regulatory milieu which includes interaction with small GTPases. We are now investigating how PLC-1 is regulated during morphogenesis. We are also investigating, using RNAi and genetics, what other signalling pathways interact with IP3 signalling during embryonic development.
In addition to our work on genes related to Alzheimer’s disease and muscular dystrophy described in other sections we have undertaken a number of collaborative projects using C. elegans as a model for understanding degenerative diseases in human. Our aims have been to use C. elegans to investigate the mechanistic basis of the disease and as a tool to screen for therapeutic agents. In particular we have worked closely with Prof. Francesc Palau in Valencia (to develop models of Friedreich’s ataxia and other inherited mitochondrial diseases.
See publications for more details.
Caveolins are structural components of cavelolae; small invaginations in the plasma membranes of many cell types. The functions of these proteins in animals remains a subject of intense interest. C. elegans has two caveolins. We have shown that caveolin-1 is important to neurotransmission in worms (Parker et al, 2007). As part of this study we showed that mutations in human caveolin that are known to cause certain types of muscular dystrophy result in defects in transmission at neuromuscular junctions in C. elegans.
More recently we discovered that caveolin-2 is important to endocytosis and trafficking in the intestine. Caveolin-2 is an apical protein and is required for normal lipid uptake in the intestine, suggesting a conserved function in mammals and C. elegans. More surprisingly, caveolin-2 also modulates recycling events on the basal side of the cell (Parker et al, 2009). We now wish to understand the mechanistic basis of these two roles.